Lecture 9: Pertubations of the Gastrointestinal Tract PDF

🐣 Lecture 9: Pertubations of the gastrointestinal tract Explain how the liver and pancreas bud develop from the gut tube, including molecular regulation. Development of the gut tube The gu...

🐣 Lecture 9: Pertubations of the gastrointestinal tract Explain how the liver and pancreas bud develop from the gut tube, including molecular regulation. Development of the gut tube The gut tube forms from the endoderm As the gut tube develops, it differentiates into various regions of the digestive system, including the oesophagus, stomach, small intestine, large intestine, liver, and pancreas. Development of these regions involves specific patterns of gene expression, which are represented in diagrams with different colours and patterns. The development of the GI tract follows an anterior (front) to posterior (back) direction. Various signalling processes regulate this development, including the role of Hox genes and other homeobox-related transcription factors, Lecture 9: Pertubations of the gastrointestinal tract 1  which are crucial in controlling gene expression during this process. Regional specification of gut endoderm through interactions with surrounding tissues Why study its development? Understanding how the intestinal tract normally develops can provide insight into the basis of birth defects. Developing therapies for intestinal diseases depends on developing a knowledge of how these tissues normally develop. Regenerative and stem cell therapies aim to recapitulate the normal steps in tissue development in order to produce the desired cell type. Eg Pancreatic beta cells Formation of the gut tube lining from endoderm The gut tube is initially formed by both longitudinal and transverse folding of the embryo Lecture 9: Pertubations of the gastrointestinal tract 2  Longitudinal folding Occurs between days 21 and 24 of human development Bending of the embryo along its length, which brings the head and tail of the embryo closer together The amniotic cavity pushes in at the cranial and caudal ends As the head and tail ends move toward each other, causing the opening to the yolk sac to narrow - this narrowing results in the vitelline (yolk sac) duct becoming smaller and more localised to the midgut. Initially, the gut is divided into three regions: the foregut, midgut, and hindgut. These regions are connected to the yolk sac, a structure that provides nutrients to the developing embryo. Transverse folding This folding is influenced by the growth of somites (blocks of mesoderm that will develop into muscles and vertebrae) and the movement of the amniotic cavity, which pushes the sides of the embryo inward Lecture 9: Pertubations of the gastrointestinal tract 3  Transverse folding occurs as a consequence of the enlargement of the somites The combination of transverse and longtitudinal folding results in the formation of the gut tube Early establishment of the primitive gut tube Adult derivatives FOREGUT Lecture 9: Pertubations of the gastrointestinal tract 4  Pharynx Oesophagus Stomach Upper duodenum Liver, gall bladder, pancreas MIDGUT Lower duodenum Jejunum and ileum Caecum and appendix Ascending colon Cranial half of transverse colon HINDGUT Caudal half of the transverse colon Descending colon Rectum Pancreas and liver development The endoderm forms the lining of 3 organs that develop caudal to the stomach: liver, gallbladder and pancreas. These organs originate as buds from the duodenum Liver development: Liver development can be induced in any part of the endoderm if exposed to signals from the cardiac mesoderm (the tissue that will form the heart) → these signals direct the endoderm to become liver tissue. However, the notochord (a structure that provides signals and support during early development) inhibits liver formation This is why the liver only forms in the region of the gut endoderm closest to the cardiac mesoderm and far enough from the notochord to avoid its inhibitory effects. Pancreas development: Lecture 9: Pertubations of the gastrointestinal tract 5  Dorsal pancreas development is activated by the notochord through activin and Fgf from the notochord repressing expression of sonic hedgehog (shh) in the dorsal endoderm. Additional signals from blood vessels (particularly the aorta and vitelline veins) around the developing pancreas Ie. the blood vessel endothelium (the inner lining of the blood vessels) releases molecular signals that promote the expression of key pancreatic genes such as PDX1 and PTF1A. Pancreas has both exocrine (producing digestive enzymes) and endocrine (producing hormones like insulin) components. The development of the endocrine part, specifically the islets of Langerhans, which secrete insulin, is heavily influenced by blood vessels. The blood vessels surrounding the pancreas are essential not only for supplying nutrients but also for the proper development and function of insulin-secreting cells, as these blood vessels will later carry hormones into the bloodstream. Vitelline ducts variation in different species In chicken embryos, there are paired vitelline veins, which can lead to the development of two lobes of a ventral pancreas. In mice, however, one of the vitelline veins (the left one) is lost during development, resulting in the formation of only a single ventral pancreatic bud. Lecture 9: Pertubations of the gastrointestinal tract 6  Heterotopic tissue - the presence of the tissue outside its normal location Pieces of gastric mucosa or pancreatic tissue found in other organs → Can cause ulcers in unexpected locations. ^^ Could be due to the inappropriate expression of genes Eg) mice null for Hes1 (Notch signalling mediator) have ectopic pancreas in stomach, duodenum. Describe how a bilobed ventral pancreas could result in annular pancreas. Annular pancreas Lecture 9: Pertubations of the gastrointestinal tract 7  A congenital condition where a ring of pancreatic tissue encircles the duodenum, the first part of the small intestine This abnormality can lead to duodenal obstruction, where the passage of food through the duodenum is blocked, causing severe digestive issues. Normally, the ventral pancreas rotates to the right side and merges with the dorsal pancreas to form a single organ HOWEVER - it's hypothesised that a bilobed ventral pancreas could form —meaning there are two lobes instead of one. These two lobes could potentially wrap around both sides of the duodenum, and as they merge with the dorsal pancreas, they could create a ring of pancreatic tissue around the duodenum, leading to obstruction. In the context of annular pancreas, a lack of Shh signaling has been associated with the development of this condition. In humans, mutations in the Shh gene can lead to duodenal stenosis (narrowing of the duodenum) and imperforate anus (a birth defect where the opening to the anus is missing or blocked). Both of these conditions are also associated with annular pancreas. Lecture 9: Pertubations of the gastrointestinal tract 8  Ihh is another member of the hedgehog signaling family. In mice, loss of Ihh signaling has been linked to ectopic branching of the ventral pancreas, which could also contribute to the development of an annular pancreas. Explain how left-right asymmetry can affect midgut rotation, and the spectrum of anomalies that can result from abnormal rotation. Rotation of the midgut The gut is suspended by the dorsal mesentery - suspending the developing gut from the posterior abdominal wall in the embryo. The mesentery is crucial for maintaining the proper positioning and orientation of the gut during rotations. It helps to anchor the gut, ensuring that it stays in place as it undergoes the complex movements of rotation. Two Phases of Gut Rotation: 1) First Rotation (90 Degrees Anti-clockwise): As the midgut elongates and temporarily extends into the umbilical cord (a process known as physiological herniation), it undergoes a 90-degree anti-clockwise rotation around the superior mesenteric artery. 2) Second Rotation (180 Degrees Anti-clockwise): After the midgut has elongated and rotated 90 degrees, it begins to return from the umbilical cord back into the abdominal cavity. During this process, the gut undergoes an additional 180-degree anti-clockwise rotation. Lecture 9: Pertubations of the gastrointestinal tract 9  Left-right asymmetry in rotation The rotation of the gut is initiated and driven by several factors: Greater Growth in the Cranial Limb: The cranial (upper) limb of the developing midgut grows more rapidly than the caudal (lower) limb, contributing to the rotation process. Left-Right Asymmetry: Another significant factor is left-right asymmetry, which is the developmental process where the left and right sides of the body exhibit different gene expression patterns and structures. Although the gut tube itself is a singular structure, the mesentery is derived from both the left and right sides of the embryo, which merge together. This merging results in the mesentery having distinct left and right components, each with different structural and molecular characteristics. Left side has: Lecture 9: Pertubations of the gastrointestinal tract 10  Express Pitx2 - a gene that plays a key role in establishing left-right asymmetry → leads to changes in gene expression and cellular structures on the left side Pitx2 drives the formation of a thicker columnar epithelium Expression of N-cadherin Mesenchymal condensation (a process where mesenchymal cells aggregate and form denser tissue). Right side has: Has a thinner, more squamous-like epithelium This asymmetry in thickness and structure between the left and right sides contributes to the physical forces that pull and rotate the gut Hypothesis for gut rotation → differential expression of genes like Pitx2 and the resulting structural differences in the mesentery create a mechanical force that pulls the gut to the left, initiating its anti-clockwise rotation Lecture 9: Pertubations of the gastrointestinal tract 11  Fusion to body wall As the gut re-enters the abdominal cavity, parts of the mesentery (the membrane that suspends and supports the gut) come into contact and fuse with the gut wall. The regions of the gut that remain suspended within the peritoneal cavity, covered by the mesentery on both sides → intraperitoneal Some regions of the gut, once intraperitoneal, become secondarily retroperitoneal as they adhere to the posterior abdominal wall. Eg) Ascending colon & descending colon Abnormal rotation of the gut tube Lecture 9: Pertubations of the gastrointestinal tract 12  Complications: Volvulus (Gut Strangulation): Definition: Volvulus refers to the twisting of a section of the gut around itself, which can obstruct blood flow. Consequences: Twisting can lead to strangulation of the blood vessels, causing ischemia (lack of blood supply) and tissue damage. It can also cause obstruction, resulting in pain and inability to pass food. Treatment: Surgical intervention is often required to resolve volvulus and restore normal blood flow. Non-Rotation: Definition: Non-rotation occurs when the gut fails to complete its normal anti-clockwise rotation. This can result in the primary intestinal loop not rotating correctly. Appearance: This condition can lead to the gut being positioned on the left side of the abdomen, a situation sometimes called "left- sided colon." Reversed Rotation: Definition: Reversed rotation is when the second 180-degree rotation occurs in the opposite (clockwise) direction. Consequences: This abnormal rotation can lead to misplacement of the gut and potentially obstruct the normal arrangement and function. Sub-hepatic Cecum: Definition: Sub-hepatic cecum occurs when the cecum (the beginning of the large intestine) is fixed just below the stomach (pylorus). Consequences: This can result in the small intestine being tethered by a narrow mesentery, increasing the risk of intestinal obstruction. Lecture 9: Pertubations of the gastrointestinal tract 13  Factors affecting rotation: Left-Right Signaling: Role: Left-right signaling, such as through the Pitx2 gene, is crucial for proper gut rotation. Disruptions can lead to abnormalities in rotation. Smooth Muscle Formation: Importance: Proper smooth muscle formation in the gut wall is essential for normal gut rotation. Differential Growth: Role: The differential growth of different parts of the gut helps drive and regulate proper rotation. Describe the physiological herniation of the gut during embryonic development, and contrast the different types of abnormal herniation (umbilical hernia, omphalocoele and gastroschisis). Physiological Herniation: Normal Occurrence: At 7-8 weeks of gestation, the gut temporarily herniates into the umbilical cord. This is a normal part of development, and the gut typically returns to the abdominal cavity by the end of this period. Types of abnormal congenital hernias: Lecture 9: Pertubations of the gastrointestinal tract 14  Umbilical Hernia: Definition: A small portion of the bowel protrudes through the umbilical ring but is covered by skin. Severity: This type is generally less severe and often resolves spontaneously as the child grows. Since it’s covered by skin, it usually doesn’t pose significant issues. Omphalocele: Definition: In this condition, the intestines, usually the mid-gut, fail to return to the abdominal cavity after the physiological herniation. Covering: The protruding organs are covered by an amniotic membrane but not by muscle or skin. Issue: This can lead to problems because the abdominal contents are exposed to the amniotic fluid and are not protected by the skin or muscle. Lecture 9: Pertubations of the gastrointestinal tract 15  Gastroschisis: Definition: The intestines protrude through a defect in the abdominal wall, usually to the right of the umbilicus. Covering: The intestines are not covered by an amniotic membrane, skin, or muscle, making this condition more exposed than omphalocele. Issue: Since there’s no covering, the intestines are directly exposed to the environment, which can lead to complications and infections. Describe the consequences that can occur if remnants of the vitelline duct remain after embryogenesis. Vitelline duct Initially the midgut is connected to the yolk sac → this connection becomes the vitelline duct. The vitelline duct normally regresses (between 5th - 8th week) Lecture 9: Pertubations of the gastrointestinal tract 16  Meckel's Diverticulum - a small, blind-ended pouch that remains if the vitelline duct (or omphalomesenteric duct) doesn't regress completely during fetal development Mostly asymptomatic, but can be inflamed or ulcerated. In some cases, the diverticulum remains connected to the umbilicus (belly button) via a fibrous cord Can create a potential for complications if the intestine twists around this cord, leading to a condition called volvulus Can creates a fistula (an abnormal connection) between the ileum (part of the small intestine) and the umbilicus - called umbilicoileal fistula Meckel’s diverticulum is the most common congenital digestive abnormality Lecture 9: Pertubations of the gastrointestinal tract 17  Explain how the urogenital sinus is separated from the rectum, and anomalies that can occur following abnormal development of the distal hindgut. Primitive Cloaca: The hindgut initially opens into the primitive cloaca, a common cavity where the early digestive and urogenital systems are connected. This cavity is lined with endodermal tissue Urorectal septum then separates urogenital sinus & rectum Urorectal Septum: A mesodermal structure known as the urorectal septum begins to invaginate (fold inwards) and moves between the developing rectum and the urogenital sinus (the part of the cloaca that will eventually become the bladder and parts of the genitalia). Separation: The urorectal septum eventually separates the cloaca into two distinct systems: the rectum (posteriorly) and the urogenital sinus (anteriorly). This separation creates two distinct openings—one for the digestive system and one for the urogenital system. Perineal Body Formation: Perineal Body: After the separation is complete, the urorectal septum forms a structure known as the perineal body at the cloacal membrane, which is located between the future anus and urogenital openings. Lecture 9: Pertubations of the gastrointestinal tract 18  Epithelial Lining of the Gastrointestinal Tract: Endodermal Origin: The epithelial lining of most of the gastrointestinal tract, including the rectum, is derived from the endoderm. Ectodermal Contribution: The lining of the very end of the anal canal is derived from the ectoderm, forming a membrane at the base. The anal canal initially has an endodermal and ectodermal membrane that covers it. This membrane usually breaks down after the seventh week of development, allowing the formation of the anal lumen (the opening of the anus). By about the ninth week of development, the anal lumen fully forms and becomes a continuous tube. The upper half of the anal canal is derived fromendoderm, while the lower half is derived from ectoderm. Dentate (Pectinate) Line: Definition: The dentate line (or pectinate line) is the junction where the endoderm-derived tissue (upper part of the anal canal) meets the ectoderm-derived tissue (lower part of the anal canal). Blood Supply and Innervation: Above and below the dentate line, the tissues have different blood supplies and nerve innervations, which means Lecture 9: Pertubations of the gastrointestinal tract 19  they respond differently to conditions such as hemorrhoids. Hemorrhoids: Hemorrhoids above the dentate line (internal hemorrhoids) are generally not painful because they are innervated by visceral nerves. In contrast, hemorrhoids below the line (external hemorrhoids) are more painful because they are innervated by somatic nerves, which are more sensitive. Imperforate anus/anal atresia Lack of an Anal Opening (Imperforate Anus): Cause: One possible cause of this condition is the persistence of the cloacal membrane, which is a membrane that normally breaks down to allow the formation of the anal opening. If this membrane does not open up, it results in an imperforate anus, where there is no external opening for the rectum. Visual: In a baby with an imperforate anus, there is no visible anal opening, and this condition requires surgical intervention to create a proper opening. Atresia of the Rectum: Definition: Atresia refers to a condition where a body passage is abnormally closed or absent. In the case of rectal atresia, the rectum does not fully develop or extend properly, resulting in a blockage where the rectum ends in a blind pouch rather than opening externally. Lecture 9: Pertubations of the gastrointestinal tract 20  Severity: The severity of atresia can vary, depending on how much tissue is obstructing the pathway or how much of the rectum is underdeveloped. Abnormal Connections Between Urogenital and Rectal Tissues: Cause: During normal development, the urorectal septum separates the urogenital system from the rectal system. However, if this process is incomplete or abnormal, there can be improper connections or fistulas between these systems, leading to complications. Deletion of both Hoxa13 and Hoxd13 in mice cause defects in cloacal partitioning and anal sphincter. Role: Hox genes are critical in the proper formation and partitioning of the cloaca into separate urogenital and rectal regions. Mutations in these genes can lead to defects in the urorectal septum, resulting in improper separation of the digestive and urogenital systems, as well as defects in the formation of the anal sphincter. Mutations in Shh and Gli2 result in lack of anus (colon ends in blind sac) Role: The Shh signaling pathway is crucial for the proper development of many body structures, including the formation of the anus. Mutations in this pathway can cause severe defects, such as a condition where the colon ends in a blind sac, meaning there is no connection between the rectum and the external body, leading to an imperforate anus. Lecture 9: Pertubations of the gastrointestinal tract 21  Hindgut fistulas (abnormal connection between two body parts) and atresias (absence or closure of a normal body passage) Many cases of anal atresia have a fistula connecting portion of hindgut to another structure in urogenital sinus region. Lecture 9: Pertubations of the gastrointestinal tract 22  Explain how Hirschsprungs disease results from improper development of the neural crest. Enteric nervous system development Enteric neural crest cells (ENCCs) primarily originate from the vagal neural crest, located around the neck region (cervical area) of the developing embryo Migration process: ENCCs migrate from the vagal region into the gut, beginning at the oral (mouth) end and moving towards the anal end As the cells migrate along the gut, they colonize it, contributing to the formation of the enteric nervous system throughout the gastrointestinal tract. Stages of Migration in Mice: Lecture 9: Pertubations of the gastrointestinal tract 23  E9.5: The neural crest cells begin their migration into the developing gut. E10.5: The gut is undergoing physiological herniation (a temporary stage where the gut protrudes into the umbilical cord due to rapid growth), and the neural crest cells continue their migration. As the gut returns to the abdominal cavity, ENCCs migrate further and populate the entire length of the gut. Contribution of Sacral Neural Crest Cells: In addition to the vagal neural crest cells, a smaller population of sacral neural crest cells (originating from the lower part of the spinal cord) also contributes to the ENS. However, the sacral neural crest cells only start contributing significantly after the vagal neural crest cells have already migrated to the distal (far) end of the gut. They mainly give rise to some of the neurons and glia in the distal parts of the gut. Enteric nervous system Structure of the Enteric Nervous System (ENS): The ENS forms two major networks of neurons, called plexi (or plexuses), that run along the entire length of the gut: Lecture 9: Pertubations of the gastrointestinal tract 24  Myenteric Plexus (Auerbach's Plexus): Located between the two layers of the muscularis externa, this plexus primarily controls the gut's motility, including the rhythmic contractions known as peristalsis. Submucosal Plexus (Meissner's Plexus): Found in the submucosa, this plexus regulates functions such as blood flow, secretion of digestive enzymes, and absorption in the gut. Fishnet Stockings Analogy: The plexuses are described as looking like "fishnet stockings," meaning they consist of interconnected neuronal cell bodies and fibers that create a net-like structure across the gut wall. This network allows for coordinated communication and control across different parts of the gut. Regulation of Gut Function: The ENS plays a crucial role in regulating several aspects of gut function: Peristalsis: The coordinated contraction and relaxation of gut muscles that propels food along the digestive tract. The myenteric plexus is primarily responsible for this process. Secretion: The submucosal plexus controls the secretion of digestive enzymes and fluids, which are essential for breaking down food Autonomous Functioning: The ENS is sometimes referred to as the "second brain" because it contains a vast number of neurons—almost as many as in the spinal cord—and can operate independently of the central nervous system (CNS). Although it is modulated by the sympathetic and parasympathetic branches of the autonomic nervous system (which can speed up or slow down digestive processes), the ENS itself can control digestion autonomously. This independence allows the digestive Lecture 9: Pertubations of the gastrointestinal tract 25  system to function without conscious thought, ensuring that the body efficiently processes and absorbs nutrients. Hirschsprung’s Disease Hirschsprung's disease occurs when neural crest cells fail to migrate all the way to the end of the gut during development. Neural crest cells are essential for forming the ENS, which controls peristalsis—the rhythmic contractions that move food through the digestive tract. In Hirschsprung's disease, there is a region of the gut without an ENS (aganglionic region), meaning this area cannot regulate muscle contractions properly. Effect on the Gut: The absence of the ENS in a section of the gut results in that area being constantly constricted. The muscles in this section cannot relax, causing a blockage. Food can enter the gut but cannot pass through the constricted area, leading to a build-up of food and waste above the blockage. Symptoms and Physical Manifestation: Lecture 9: Pertubations of the gastrointestinal tract 26  The constricted region with no ENS leads to a condition known as megacolon. The section of the gut above the constriction becomes swollen because food and waste accumulate there. This swollen area, however, contains normal enteric neurons and is not the source of the problem. The actual issue lies in the constricted segment at the end of the gut, where there is a lack of enteric neurons. Complications: If left untreated, the build-up of waste in the megacolon can lead to dangerous complications. The gut may swell to the point where it tears or leaks, causing sepsis, a life-threatening infection that can spread throughout the body. Lecture 9: Pertubations of the gastrointestinal tract 27  Hirschsprungs disease – role of GDNF pathway GDNF (Glial Cell-Derived Neurotrophic Factor) is crucial for the development of the enteric nervous system (ENS). It is responsible for: Survival of enteric neural crest cells. Migration of these cells along the gut. Proliferation (increasing the number of cells). Lecture 9: Pertubations of the gastrointestinal tract 28  Differentiation (cells becoming specialized). The pathway involves GDNF forming a dimer (a molecule made up of two identical subunits). This dimer binds to a receptor called GFRα1 (GDNF family receptor alpha 1), which must pair with another receptor, RET (a receptor tyrosine kinase), to activate downstream signaling that is crucial for ENS development. Mice study: Knockout Mice (Mice without GDNF or RET genes): Mice lacking the GDNF or RET gene completely fail to develop enteric neurons, indicating the essential role of these genes in ENS development. Heterozygous Mice (Mice with one functional and one non- functional RET gene): These mice appear normal and do not show defects in the ENS, indicating that in mice, one functional RET gene is sufficient for normal ENS development. Differences Between Mice and Humans: In humans, individuals who are heterozygous for a mutation in RET (having one normal and one mutated RET gene) can develop Hirschsprung's disease. This suggests that humans may require a higher level of RET function than mice. The difference might be due to the fact that humans have a longer gut than mice, meaning that the process of neural crest cells migrating along the gut takes longer and might require more RET signaling for proper development. Threshold of RET Function: In mice, if RET levels are reduced to about 30-40%, they develop Hirschsprung's disease. This highlights the importance of maintaining a certain threshold level of RET for the proper migration of neural crest cells and the formation of the ENS. Hirschsprung’s disease – complex multigenic disorder Lecture 9: Pertubations of the gastrointestinal tract 29  Hirschsprung's disease occurs more frequently in males than in females There is a 4:1 male:female sex bias The disease is influenced by both genetic mutations and environmental factors Incomplete Penetrance - refers to the fact that not everyone with a genetic mutation associated with Hirschsprung's disease will actually develop the disease. For example, within the same family, individuals with the same missense mutation in the RET gene can have different outcomes: One individual may have long-segment Hirschsprung's disease, where a large portion of the gut is affected. Two others might have short-segment Hirschsprung's disease, with a smaller region affected. Another might not develop the disease at all. The variability in how Hirschsprung's disease manifests can be attributed to several factors: Multiple Genes: Other genes besides RET may influence the development and severity of the disease. Environmental Factors: Non-genetic factors, such as the prenatal environment, could impact the development of the enteric nervous system. Epigenetic Factors: Changes in gene expression that do not involve alterations to the DNA sequence (epigenetics) might play a role. Sex Bias: As mentioned, the disease affects males more frequently, suggesting that gender may also influence the risk and severity of the condition. Discuss the role of the microbiota in the development and maturation of the gastrointestinal tract. Microbiota Lecture 9: Pertubations of the gastrointestinal tract 30  The microbiota consists of bacteria that live in the gastrointestinal tract, particularly in the colon. These bacteria are crucial for digesting food and providing nutrients that the human body cannot extract on its own. Interestingly, there are more bacterial genes in the human body than human genes. Although the microbiota likely doesn't play a significant role in development before birth, it becomes essential for normal functioning and immune development after birth. The microbiota is also involved in regulating the immune system, the nervous system, and nutrient absorption. Variability of Microbiota: The composition of the microbiota varies significantly between individuals, primarily influenced by diet. The idea that the uterus is sterile has been challenged by recent studies showing minimal bacterial colonization before birth. However, the majority of microbiota colonization happens after birth. Influence of Birth Method: The mode of delivery during birth impacts the initial microbiota colonization: Vaginal birth exposes the baby to bacteria from the vaginal canal. Caesarean birth exposes the baby to bacteria primarily from the skin. This difference in initial exposure could potentially influence the baby's developing microbiota and overall health. Diet's Role in Microbiota Development: A baby's microbiota is heavily influenced by its diet, such as whether the baby is breastfed or bottle-fed. The microbiota undergoes significant changes during the first two years of life, stabilizing afterward. Lecture 9: Pertubations of the gastrointestinal tract 31  Germ free mice Germ-free mice are bred and raised in an environment without any bacteria, often delivered by caesarean section and kept in sterile conditions. These mice show significant differences in immune system development, nervous system function, and nutrient absorption compared to mice with normal bacterial exposure. Some effects of bacteria (gut microtobia) on gut development Increase development of small intestinal capillary networks - crucial for proper nutrient absorption and gut function. Development of immune system in gut Lecture 9: Pertubations of the gastrointestinal tract 32  Affects the presence and function of glial cells in crypt/villi - involved in supporting neurons and maintaining gut function. Maintenance of neural-immune interactions in ENS Impact on brain development - Comparisons between germ-free mice (mice without any bacteria) and those with a normal microbiota reveal differences in brain activity and gene expression. For instance, germ-free mice exhibit changes in brain activity and gene expression compared to mice with a healthy, diverse microbiota. Impact of microbiota Effect on immune development Effect on nervous system (enteric nervous system and brain) Lecture 9: Pertubations of the gastrointestinal tract 33  Behaviour Effect on gut epithelium Intestinal (and overall) health An imbalance in the microbiota, known as dysbiosis, where harmful bacteria outnumber beneficial ones, can disrupt gut function and contribute to various health problems. Dietary Recommendations: Healthy Diet: A diet rich in vegetables and whole grains supports a healthy microbiota. This is because such foods promote the growth of beneficial bacteria. Lecture 9: Pertubations of the gastrointestinal tract 34  Mediterranean Diet: This diet, which emphasizes whole grains, vegetables, fruits, nuts, and healthy fats, has been shown to improve the diversity and health of gut bacteria. Lecture 9: Pertubations of the gastrointestinal tract 35